Rheumatic Heart Disease (RHD)

Epidemiology

• Global burden: RHD affects over 40.5 million people worldwide and caused approximately 305,651 deaths in 2019, resulting in 10.7 million DALYs lost annually - almost entirely in endemic countries.
• Incidence of ARF: ~19/100,000 globally; lowest in North America/Western Europe (<10/100,000), highest in Eastern Europe, Middle East, Asia, Africa, and Oceania.
• Age: Most common between ages 5-30; peak onset of ARF is 5-15 years.
• Sex: Women are ~1.8 times more susceptible to developing RHD, and disease is more severe in females than males.
• High-burden regions: Central sub-Saharan Africa, South Asia, and Oceania (particularly indigenous populations).
• India: Prevalence of 5-7 per 1000 in the 5-15 age group; RHD constitutes 20-30% of hospital admissions for cardiovascular disease.
• Declining in affluent nations: But persists in pockets of poverty even in high-income countries.

Pathophysiology

Molecular Mimicry - The Core Mechanism

1. GAS pharyngitis triggers antibody production against streptococcal M-protein and N-acetyl-glucosamine (streptococcal carbohydrate).
2. These antibodies cross-react with cardiac myosin, tropomyosin, and laminin in valve tissue - a phenomenon called molecular mimicry.
3. Cross-reactive antibodies bind to valvular endothelium and basement membrane, upregulating adhesion molecules including VCAM-1 (vascular cell adhesion molecule-1).
4. VCAM-1 interacts with VLA-4 (very late activation antigen-4) on CD4+ T lymphocytes, facilitating their infiltration into heart tissue.
5. Chemokines including CCL1/I-309 and CXCL9/Mig are highly expressed in valvular tissue, mediating both CD4+ and CD8+ T cell infiltration.
6. Cardiac myosin is the major autoantigen; ~63% of intralesional T cell clones in valve tissue recognize light meromyosin (LMM) peptides.

Pathological Hallmark: The Aschoff Body

• A central zone of fibrinoid necrosis
• Anitschkow (caterpillar) cells - modified macrophages with characteristic nuclei
• Surrounding mononuclear infiltrate (lymphocytes, plasma cells)

Valve Involvement

• Mitral regurgitation is the most common early lesion.
• Mitral stenosis develops from progressive scarring - RHD is the most common cause of MS worldwide.
• Aortic involvement: regurgitation more common than stenosis.

Acute Rheumatic Fever (ARF) - Clinical Features

1. Arthritis (Most Common - 65-75%)

• Migratory polyarthritis - large joints (ankles, knees, elbows, wrists)
• Begins asymmetrically in lower limbs before spreading to upper limbs
• Pain is disproportionate to physical signs (opposite to Lyme arthritis)
• Resolves completely within 4 weeks; if persistent, consider JIA or SLE
• In high-risk populations (India, Australia, Fiji): monoarthritis occurs in 17-25%
• Jaccoud arthropathy: rare chronic post-RF arthropathy with swan neck deformity, ulnar deviation - no erosions on X-ray

2. Carditis (35-72% clinical; 18% subclinical on echo)

• Pancarditis: affects endocardium, myocardium, and pericardium
• Presents as: new murmur, tachycardia out of proportion to fever, pericardial friction rub, cardiomegaly, or heart failure
• Subclinical carditis detectable by echocardiography (important addition in 2015 Jones Criteria revision)
• Most likely to resolve in the first year after acute episode

3. Sydenham's Chorea (10-30%)

• Involuntary, purposeless movements of face, trunk, and extremities
• Emotional lability, muscle weakness
• Appears late (up to 6 months after GAS infection - "pure chorea")
• Can occur in isolation without other manifestations

4. Erythema Marginatum (<5%)

• Fleeting, non-pruritic, macular rash with pale centers and red margins
• Spreads centrifugally on trunk and proximal limbs (not face)
• Evanescent - may come and go within hours

5. Subcutaneous Nodules (<5%)

• Firm, painless nodules over bony prominences (elbows, wrists, knees, ankles, spinous processes)
• Associated with severe carditis
• Resolve spontaneously within weeks

Diagnosis: Revised Jones Criteria (2015 AHA)

Major Criteria

Minor Criteria

Echocardiographic Criteria for Rheumatic Valvulitis (WHO/WHF)

• Seen in at least 2 views
• Jet length ≥2 cm in at least one view
• Peak velocity >3 m/sec
• Pansystolic jet in at least one envelope

Management

Acute Phase

Secondary Prophylaxis (Critical for preventing RHD progression)

2024 Cochrane Review (PMID: 39312290): Confirmed that long-term benzathine penicillin G prophylaxis reduces ARF recurrence and prevents progression to RHD. Adherence remains a major challenge globally (meta-analysis PMID: 39542478 found suboptimal adherence in many settings). A 2025 meta-analysis (PMID: 40333929) found severe adverse reactions to benzathine penicillin G are rare (0.2-2.1/1000 injections), supporting its continued use.

Chronic RHD - Natural History and Complications

• Progressive valvular scarring leads to severe disease in the 3rd-4th decade of life in untreated patients
• Premature death by age 35 or earlier without treatment
• Major complications:
  • Mitral stenosis - breathlessness, hemoptysis, pulmonary hypertension, right heart failure
  • Atrial fibrillation - from left atrial enlargement (major cause of stroke)
  • Infective endocarditis - RHD is a leading risk factor in developing countries
  • Heart failure - systolic and/or diastolic
  • Pulmonary hypertension
  • Thromboembolism/stroke - especially with AF and MS
• Variables predicting severity: number of previous ARF attacks, delay before starting therapy, female sex
• 60-80% of mitral insufficiency resolves with adherent prophylaxis

Surgical/Interventional Options for Chronic RHD

Prevention

• Primordial: Address social determinants - overcrowding, poverty, poor sanitation
• Primary: Treat GAS pharyngitis with antibiotics within 9 days of onset (prevents first episode of ARF)
• Secondary: Long-term benzathine penicillin G after established ARF/RHD
• Echocardiographic screening: Population-based screening in endemic regions detects subclinical RHD and guides prophylaxis to reduce disease progression (prevalence 0.3-5.7 per 1000 by echo vs. lower by auscultation alone)

Key Points Summary

1. RHD = autoimmune sequela of GAS pharyngitis via molecular mimicry
2. Pathognomonic lesion = Aschoff body (Anitschkow cells)
3. Mitral valve affected in virtually 100%; MR most common early, MS most common late
4. Diagnosis by 2015 revised Jones Criteria (requires preceding GAS evidence + major/minor manifestations)
5. Treatment: eradicate GAS + anti-inflammatory (aspirin) + manage carditis
6. Secondary prophylaxis with benzathine penicillin G is the most important intervention to prevent progression
7. RHD remains a leading preventable cause of cardiovascular mortality in low-income countries, affecting >40 million people globally